Thiaindane derivatives



United States Patent The present inevntion relates to2-oxo-3z3-di-(para-hydroxyphenyl)-l-thiaindanes substituted in thethiaindane residue, and their esters and phenolates.

The new compounds contain in the thiaindane residue preferably halogenatoms such as fluorine, chlorine or bromine atoms, or nitro groups andif desired also lower alkyl groups such as methyl, ethyl, n-propyl orisopropyl, butyl or pentyl groups, or also lower alkoxy such as methoxy,ethoxy or propoxy groups.

Esters of the new compounds are, for example, those of alkanecarboxylicacids, for example of lower alkanecarboxylic acids such as acetic acid,propionic acid, butyric acid or trimethylacetic acid. Suitablephenolates are the salts with bases, for example, those of alkali metalsor alkaline earth metals such as sodium, potassium or calcrum.

The new compounds possess valuable properties; they act, for example,against bacteria and fungi, for example against dermatophytes, Candidaalbz'cans and Gram-positive bacteria. Accordingly, they can be used moreespecially as disinfectantsor preservatives.

Special mention deserve compounds of the formula in which R representshalogen, more especially chlorine, and R has the same meaning as R orrepresents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms.

The new thiaindanes are prepared by as such known methods, for exampleby condensing a substituted 2:3-dioxo-l-thiaindane with phenol and, ifdesired, resulting hydroxy compounds or their phenolates are transformedone into the other or into the esters.

The condensation is advantageously carried out in the presence of acondensing agent, such as anhydrous sulfuric or phosphoric acid,toluenesulfonic acid, zinc chloride, aluminum chloride, tintetrachloride or a phosphorus halide, in the presence or absence of asolvent or diluent, such as benzene or toluene. It is of advantage touse an excess of phenol so that it can serve at the same time as solventfor the thiaindane component. It is of advantage to work at roomtemperature or, if necessary, at a higher or lower temperature underatmospheric or superatmospheric pressure, or in the presence of an inertgas such as nitrogen.

The conversionof the hydroxyl compound to an ester thereof is carriedout in the known manner, for example by reaction with a suitable acid ora functional derivative thereof suitable for the esterification, such asan ester, halide or more especially anhydrifite, in the presence orabsence of a solvent or diluent and/or of an esterification catalyst.

Depending on the reaction conditions employed the hydroxyl compounds areobtained in the free form or in the form of their phenolates. From thephenols the phenolates can be obtained in the conventional manner, forexample those of the alkali or alkaline earth metals.

3,178,449: Patented Apr. 13, 1965 The starting materials are known orcan be prepared by known methods.

The new compounds may be used as disinfectants and preservatives in awide range of spheres. Inter alia, they are suitable for disinfectingthe skin, for example the hands, instruments, bandages, underwear or thelike, and also for disinfecting or preserving foodstuffs orfeedingstufls. They may be used by themselves or in admixtures, insolution or as emulsion and/or together with other active or inertsubstances as ointments or in the form of dry powders.

The following examples illustrate the invention.

Example 1 A mixture of 10 grams of2:3-dioxo-5-methyl-6-chlorol-thiaindane and 50 grams of phenol istreated with 10 cc. of concentrated sulfuric acid and the whole is keptfor 3 hours at room temperatures. 200 cc. of water are then added andthe reaction product is extracted with methylene chloride. After dryingover sodium sulfate and distilling off the solvent, an oily residueremains from which the excess phenol is distilled oft under a pressureof 40 mm. Hg. The remaining2-oxo-3:3-di-(parahydroxyphenyl)-5-methyl-6-chloro-l-thiaidane of theformula melts at 223-228 C. after having been recrystallized fromaqueous ethanol.

Example 2 A mixture of 10 grams of 2:3-dioxo-4:6-dichloroe7-methyl-1-thiaindane and 50 grams of phenol is treated with 10 cc. ofconcentrated sulfuric acid. After standing for 3 hours at roomtemperature the reaction product is mixed with 200 cc. of water andextracted with methylene chloride. The methylene chloride extract isdried over sodium sulfate and the solvent is then distilled off. Asemi-crystalline product is obtained from which the excess phenol isremoved by distillation under a pressure of 40 mm. Hg. The distillationresidue contains the 2-oxo-3 3-di- (para-hydroxyphenyl) -426-dichloro-7-methyl-l-thiaindane of the formula which melts at 230 C.after recrystallization from aqueous ethanol.

Example 3 The resulting solid residue is recrystallized from '3ether-l-chloroform, to yield2-oxo-3:3-di-(para-hydroxyphenyl)-4-methyl-6-chloro-l-thiaindane of theformula I C1 A in crystals melting at 245 C.

Example 4 OH O- \s O can be crystallized from aqueous ethanol, whereuponit melts at 233-234 C.

.Examplej' A mixture of 7 gramsof,2-oXo-3:3-di-(para-hydroxyphenyl)-6-methoxy 1-thiaindane and 50 cc.of acetic anhydride is heated for 4 hours at 120 C. On cooling, 2 oxo3:3 di (para acetoXyphenyl) 6 methoxyl-thiaindane of the formula Q-o con Q-OCOCI-n separates out in crystalline form. After having beenrecrystallized from glacial acetic acid it melts at 199- 200 C.

Exampleti A mixture of 8 grams of2-oxo-3:B-di-(para-hydroxyphenyl)-4-methyl-6-chloro-l-thiaindane and 50cc. of acetic anhydride is heated for 6 hours at 120 C. The reactionmixture is then evaporated to dryness. Crystallization of the solidresidue from ethanol yields 2-oxo- 3:3 di (para acetoxyphenyl) 4 methyl6 chlorol-thiaindane of the formula o o o on l l o CO 0... C1

in crystals melting at 157-158 C.

Example 7 A mixture of 10 grams of2:3-dioxo-l5-methyl-6-chlorothiaindane, 50 grams of phenol and 50 gramsof polyphosphoric acid is heated for 4 hours at 50 C. 200 cc. of waterare then added and the reaction product extracted with chloroform. Afterseparating the chloroform layer, the solvent is distilled off; an oilremains from which the excess phenol is removed by distillation under awater-jet vacuum. The remaining 2-ox0- 3:3 di (p hydroxyphenyl) methyl 6chlorol-thiaindane is recrystallized from ethanol-I-water and melts at224228 C.; it is identical with the product described in-Example 1.

4. Example 8 A cream containing 1% of2-oxo-3z3-di-(p-hydroxyphenyl)-4-methyl-6-chloro-l-thiaindane may beprepared with the following ingredients:

Percent 2 oxo 3:3 di (p hydroxyphenyl) 4 methyl- 6-chloro-1-thiaindane 1Water 6 Propyleneglycol 30 Polyethyleneglycols 63 For the preparation ofthe cream,2-oxo-3z3-di-(p-hydroxyphenyl)-4-rnethyl-6-chloro-l-thiaindane isdissolved in ropyleneglycol by gentle heating. The solution and thewater are stirred into the melted polyethyleneglycols and cooled to roomtemperature.

Example 9 A tincture containing 1% of2-oxo-3:Z-di-(p-hydroxyphenyl)-4-methyl-6-chloro-l-thiaindane may beprepared with the following ingredients:

2 -oxo-3:3-di-(p-hydroxyphenyl)-4-methyl 6 chloro-l-thiaindane ..pereent1 Aectone do 8 Isopropyl alcohol do 52 Water, q.s. percent by vol Forthe preparation of the tincture, 2-0xo-3z3-di-(phydroxyphenyl) 4methyl-6-chloro-l-thiaindane is dissolved in acetone; isopropyl alcoholand then water are added.

What is claimed is:

1. A member selected from the group consisting of a compound of theformula wherein R R and R each stands for a member selected from thegroup consisting of hydrogen, halogen,

nitro, lower alkyl and lower alkoxy and R stands for a member selectedfrom the group consisting ofhalogen, nitro, and lower alkoxy, anunsubstituted lower alkanecarboxylic acid ester and an alkali metal andalkaline earth metal phenolate thereof.

2. A compound of the formula R! Q OH l s o R wherein R and R each standsfor halogen.

3. A compound of the formula containing 1 to 4 carbon atoms.

4. A compound of the formula wherein R stands for halogen.

5. 2-Oxo-3:3-di-(para-hydroxyphenyl) 5 methyl-6- chloro-l-thiaindane.

6. 2-Oxo-3z3-di-(para-hydroxyphenyl) 4:6 dichloro-7-methy1-1-thiaindane.

7. 2-Ox0-3:3-di-(para-hydroxypheny1) 4 methyl-6- chloro-l-thiaindane.

8. 2-Oxo-3:3-di-(para-hydroxyphenyl) 6 methoxyl-thiaindane.

9. 2-Ox0-3:3-di-(para-acetoxypheny1) 6 methoxyl-thiaindane.

10. 2-OX0-3:3-di-(para-acetoxyphenyl) 4 methyl- 6-ch1oro-1-t11iaindane.

References Cited by the Examiner UNITED STATES PATENTS 2,861,919 11/58Gilbert 16765 5 2,958,624 11/60 Bimber 167-65 2,992,232 7/61 Bloom260330.5 3,010,972 11/61 Kaiser et a1. 260330.5

OTHER REFERENCES IRVING MARCUS, Primary Examiner.

JOHN D. RANDOLPH, WALTER A. MODANCE,

Examiners.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA